Process for preparing aminocrotonylamino-substituted quinazoline derivatives

ABSTRACT

The invention relates to an improved process for preparing aminocrotonylamino-substituted quinazoline derivatives of general formula (I) 
                         
wherein the groups R a , R b , R c  and R d  have the meanings given in the claims, as well as sulphonyl derivatives of formula
 
                         
and the use thereof as synthesis components for preparing quinazolines of formula (I). The quinazoline derivatives of formula (I) are inhibitors of signal transduction mediated by tyrosinekinases and by the Epidermal Growth Factor-Receptor (EGF-R) and are therefore particularly suitable for the treatment of tumoral diseases.

The invention relates to a process for preparingaminocrotonylamino-substituted quinazoline derivatives of generalformula (I)

wherein the groups R_(a), R_(b), R_(c) and R_(d) have the meanings givenin the claims and specification.

BACKGROUND TO THE INVENTION

Quinazoline derivatives of general formula (I) are known from WO02/50043 and WO 04/074263, which describe compounds with valuablepharmacological properties, including in particular an inhibitory effecton signal transduction mediated by tyrosinekinases and an inhibitoryeffect on signal transduction mediated by Epidermal GrowthFactor-Receptor (EGF-R). Therefore, compounds of this type are suitablefor the treatment of diseases, particularly for the treatment of tumoraldiseases, diseases of the lungs and airways and diseases of thegastro-intestinal tract and the bile ducts and gall bladder.

WO 2002/50043 discloses a method of production in whichaminocrotonylamino-substituted quinazolines (I) are prepared in aone-pot reaction from the corresponding aniline component (II),bromocrotonic acid, oxalyl chloride and a secondary amine (see Diagram1).

Diagram 1:

The process is not well suited to technical use on an industrial scale,as the yields obtained are at most 50% and as a rule laboriouspurification by column chromatography is needed. Moreover the eductbromocrotonic acid is not commercially available in large amounts andthe corresponding methyl bromocrotonate is only available with a purityof about 80%.

WO 2005/037824 describes an alternative process for preparingaminocrotonylamino-substituted quinazoline derivatives of generalformula (I) by Wittig-Horner-Emmons reaction ofdialkyl-phosphonoacetamido-substituted quinazolines (III) with a2-aminoacetaldehyde (IV) (Diagram 2), while instead of the aldehyde (IV)it is possible to use the corresponding hydrate or an acetal (e.g. thediethylacetal corresponding to (IV)), from which the aldehyde isliberated (beforehand or in situ).

Diagram 2:

The educts of formula III may be obtained according to WO 2005/037824 asfollows:

Diagram 3:

Both in the prior art described above and within the scope of theinvention described hereinafter, the groups R_(a), R_(b), R_(c), R_(d),R¹ and R² have the following meanings:

R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group,

R_(b) denotes a methyl, ethyl, isopropyl, cyclopropyl, 2-methoxyethyl,tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl ortetrahydropyran-4-yl-methyl group,

R_(c) denotes a methyl, ethyl or 2-methoxyethyl group or

R_(b) and R_(c) together with the nitrogen atom to which these groupsare bound denote a morpholino or homomorpholino group optionallysubstituted by one or two C₁₋₃-alkyl groups,

R_(d) denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl,tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl ortetrahydropyran-4-yl-methyl group, and

R¹ and R² each independently of one another denote a C₁₋₄-alkyl group,for example each denote an ethyl group.

By a homomorpholino group is meant the next highest ring-homologue ofthe morpholino group, namely the group of formula

Starting from commercially obtainable 4-chloro-anthranilic acid (V),reacting with formamidine acetate (step a) produces the quinazolinone(VI), which is then nitrated using sulphuric acid and concentratednitric acid (step b). The desired regioisomer (VII) is then chlorinatedusing thionyl chloride in acetonitrile (step c) and the chlorinationproduct (IX) is reacted in situ with the corresponding amine R_(a)—NH₂(step d). The compound of formula (X) thus obtained is reacted bybase-catalysed nucleophilic substitution with R_(d)—OH to form thecompound (XI) (step e), which is in turn converted by hydrogenation intothe corresponding aminoquinazoline (XII) (step f). The aminoquinazoline(XII) is then converted by reaction with adi-(C₁₋₄-alkyl)-phosphonoacetic acid, e.g. with diethylphosphonoaceticacid, in suitable solvents such as tetrahydrofuran (THF),dimethylformamide (DMF) or ethyl acetate, after correspondingactivation, for example with 1,1-carbonyldiimidazole,1,1-carbonylditriazole or propanephosphonic anhydride, into thedialkyl-phosphonoacetamido-substituted quinazoline (III) needed for theWittig-Horner-Emmons reaction.

The process described in WO 2005/037824 also has a number of seriousdisadvantages for technical use. For example, the use of thionylchloride in Step (c) is problematic for safety reasons. The cyclic orheterocyclic alcohols needed to introduce the group R_(d) in an excessof about 2 equivalents (eq) are starting materials which are difficultto obtain or expensive, and phase transfer catalysis, for example using18-crown-6, is also needed to react them according to step (e) inDiagram 3 on an industrial scale. The reaction product has to bepurified by recrystallisation to eliminate the phase transfer catalyst.The hydrogenation of step (f) is carried out with the addition of aceticacid, if the educt contains a chlorine atom, so as to prevent theformation of dechlorinated by-products which are difficult to strip out.The addition of acetic acid causes traces of the nickel needed ascatalyst to be dissolved, and this is then entrained into the final stepand gives rise to a heavy metal problem which is unacceptable forpharmaceutical use. Moreover, the throughput of individual partialreactions is in need of improvement; for example the throughput in step(e) according to Diagram 3 is only 1/60 (1 kg of starting materialrequire a reactor volume of 60 l).

In the light of the disadvantages of the known production method asdescribed above, the problem of the present invention is to provide animproved method, suitable for synthesis on an industrial scale, whichpermits the safe preparation of aminocrotonylamino-substitutedquinazoline derivatives (I) using easily obtainable starting materialsof high purity and at a lower technical cost.

DETAILED DESCRIPTION OF THE INVENTION

The problem stated above is solved according to the invention by thefollowing process for preparing a compound of general formula

wherein R_(a) to R_(d) are as hereinbefore defined, comprising thefollowing steps

Embodiment A

-   a) reacting 7-chloro-6-nitro-3H-quinazolin-4-one

with a primary amine of formula R_(a)—NH₂ (XV), wherein R_(a) denotes abenzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, in the presenceof POCl₃,

-   b) converting the resulting compound of general formula

into the sulphonyl derivative of formula

wherein

-   R³ denotes a C₁₋₄-alkyl group wherein the hydrogen atoms may be    wholly or partly replaced by fluorine atoms, or-   a phenyl group optionally substituted by one to three substituents    selected from C₁₋₃-alkyl groups, halogen atoms, particularly    fluorine, chlorine or bromine atoms, cyano or nitro groups, while    the substituents may be identical or different, and wherein R_(a) in    the two formulae (X) and (XIII) has the meanings given under a),-   c) converting the sulphonyl derivative of formula (XIII) into a    compound of formula

by reacting with an alcohol of formula R_(d)—OH (XVI) in the presence ofa base,

-   wherein R_(a) has the meanings given under a) and R_(d) denotes a    cyclopropylmethyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl,    tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl,    tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group,-   d) reducing the compound of formulae (XI) thus obtained to the amino    derivative of formula

-   wherein R_(a) has the meanings given under a) and R_(d) has the    meanings given under c),-   e) converting the amino derivatives of formula (XII) into the    phosphonic ester of formula

-   wherein R_(a) has the meanings given under a), R_(d) has the    meanings given under c), and R¹ and R² each independently of one    another denote a C₁₋₄-alkyl group, but preferably ethyl groups,-   f) reacting the resulting phosphonic ester of formula (III) with a    hydrogen sulphite adduct of formula

wherein

-   M⁺ denotes a cation, for example the sodium ion, or a proton and-   R_(b) denotes a methyl, ethyl, isopropyl, cyclopropyl,    2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group,-   R_(c) denotes a methyl, ethyl or 2-methoxyethyl group or-   R_(b) and R_(c) together with the nitrogen atom to which these    groups are bound represent a morpholino or homomorpholino group    optionally substituted by one or two C₁₋₃-alkyl groups,    in the manner of a Wittig-Horner-Emmons reaction.

In another aspect the invention relates to the sulphonyl derivatives offormula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group and-   R³ denotes a C₁₋₄-alkyl group wherein the hydrogen atoms may be    wholly or partly replaced by fluorine atoms, or-   a phenyl group optionally substituted by one to three substituents    selected from C₁₋₃-alkyl groups, halogen atoms, particularly    fluorine, chlorine or bromine atoms, cyano or nitro groups, while    the substituents may be identical or different,    which are valuable synthesis components for preparing the    pharmacologically active quinazoline derivatives of general formula    (I).

For example R³ in formula (XIII) may denote the p-toluenesulphonyl,p-bromo-benzenesulphonyl, phenyl, p-nitro-benzenesulphonyl,methylsulphonyl, trifluoromethylsulphonyl, nonafluorobutylsulphonyl or2,2,2-trifluoroethanesulphonyl group.

The following are mentioned as particularly preferred compounds offormula (XIII):

-   (1)    4-(3-chloro-4-fluoro-phenylamino)-7-(4-methyl-phenylsulphonyl-)-6-nitro-quinazoline,-   (2)    4-(3-chloro-4-fluoro-phenylamino)-7-(4-bromo-phenylsulphonyl)-6-nitro-quinazoline,-   (3)    4-(3-chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline,-   (4)    4-(3-chloro-4-fluoro-phenylamino)-7-(4-nitro-phenylsulphonyl)-6-nitro-quinazoline,-   (5)    4-(3-chloro-4-fluoro-phenylamino)-7-(methylsulphonyl)-6-nitro-quinazoline,-   (6)    4-(3-chloro-4-fluoro-phenylamino)-7-(trifluoromethylsulphonyl)-6-nitro-quinazoline,-   (7)    4-(3-chloro-4-fluoro-phenylamino)-7-(nonafluorobutylsulphonyl)-6-nitro-quinazoline,-   (8)    4-(3-chloro-4-fluoro-phenylamino)-7-(2,2,2-trifluoroethanesulphonyl)-6-nitro-quinazoline-   (9)    4-(benzylamino)-7-(4-methyl-phenylsulphonyl-)-6-nitro-quinazoline,-   (10)    4-(benzylamino)-7-(4-bromo-phenylsulphonyl)-6-nitro-quinazoline,-   (11) 4-(benzylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline,-   (12)    4-(benzylamino)-7-(4-nitro-phenylsulphonyl)-6-nitro-quinazoline,-   (13) 4-(benzylamino)-7-(methylsulphonyl)-6-nitro-quinazoline,-   (14)    4-(benzylamino)-7-(trifluoromethylsulphonyl)-6-nitro-quinazoline,-   (15)    4-(benzylamino)-7-(nonafluorobutylsulphonyl)-6-nitro-quinazoline,-   (16)    4-(benzylamino)-7-(2,2,2-trifluoroethanesulphonyl)-6-nitro-quinazoline,-   (17)    4-(1-phenylethylamino)-7-(4-methyl-phenylsulphonyl-)-6-nitro-quinazoline,-   (18)    4-(1-phenylethylamino)-7-(4-bromo-phenylsulphonyl)-6-nitro-quinazoline,-   (19) 4-(1-phenylethylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline,-   (20)    4-(1-phenylethylamino)-7-(4-nitro-phenylsulphonyl)-6-nitro-quinazoline,-   (21) 4-(1-phenylethylamino)-7-(methylsulphonyl)-6-nitro-quinazoline,-   (22)    4-(1-phenylethylamino)-7-(trifluoromethylsulphonyl)-6-nitro-quinazoline,-   (23)    4-(1-phenylethylamino)-7-(nonafluorobutylsulphonyl)-6-nitro-quinazoline    and-   (24)    4-(1-phenylethylamino)-7-(2,2,2-trifluoroethanesulphonyl)-6-nitro-quinazoline.

The educts used in the process according to the invention and notdescribed in more detail are either known from the literature or may beprepared from precursors known from the literature by simple analogousmethods. For example, the sodium hydrogen sulphite adduct of formula(XIV) may be obtained from the corresponding acetal by liberating thecorresponding aldehyde in hydrochloric acid solution and subsequentprecipitation by the addition of NaHSO₃ solution. The diethylacetal maybe prepared from the corresponding aldehyde by conventional methods.

Specifically, the invention described in embodiment A has the followingpartial aspects B, C and D:

B) Preparation of the Synthesis Component of Formula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group and-   R_(d) denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl,    tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group, by-   a) reacting 7-chloro-6-nitro-3H-quinazolin-4-one

with a primary amine of formula R_(a)—NH₂ (XV), wherein R_(a) denotes abenzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group, in the presenceof POCl₃,

-   b) converting the resulting compound of general formula

into the sulphonyl derivative of formula

wherein

-   R³ denotes a C₁₋₄-alkyl group wherein the hydrogen atoms may be    wholly or partly replaced by fluorine atoms, or-   a phenyl group optionally substituted by one to three substituents    selected from C₁₋₃-alkyl groups, halogen atoms, particularly    fluorine, chlorine or bromine atoms, cyano or nitro groups, wherein    the substituents may be identical or different, and wherein R_(a) in    the two formulae (X) and (XIII) has the meanings given under a),-   c) converting the sulphonyl derivative of formula (XIII) into a    compound of formula

by reacting with an alcohol of formula R_(d)—OH (XVI) in the presence ofa base,

-   wherein R_(a) has the meanings given under a) and R_(d) denotes a    cyclopropylmethyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl,    tetrahydrofuran-2-yl-methyl, tetrahydrofuran-3-yl-methyl,    tetrahydropyran-4-yl or tetrahydropyran-4-yl-methyl group.

C) Preparing the Synthesis Component of Formula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group,-   R_(d) denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,    tetrahydrofuran-3-yl-oxy, tetrahydrofuran-2-yl-methoxy,    tetrahydrofuran-3-yl-methoxy, tetrahydro-pyran-4-yl-oxy or    tetrahydropyran-4-yl-methoxy group, and-   R¹ and R² each independently of one another denote a C₁₋₄-alkyl    group,    by preparing the synthesis component of formula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group and-   R_(d) denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl,    tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group,    according to the process described under B) and subsequently-   d) reducing the compound of formulae (XI) thus obtained to the amino    derivative of formula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group and-   R_(d) denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl,    tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group, and-   e) converting the amino derivatives of formula (XII) into the    phosphonic ester of formula

wherein R_(a) and R_(d) have the meanings given under d), and R¹ and R²each independently of one another denote a C₁₋₄-alkyl group.

D) Preparing a Compound of General Formula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group,-   R_(b) denotes a methyl, ethyl, isopropyl, cyclopropyl,    2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group,-   R_(c) denotes a methyl, ethyl or 2-methoxyethyl group or-   R_(b) and R_(c) together with the nitrogen atom to which these    groups are bound denote a morpholino or homomorpholino group    optionally substituted by one or two C₁₋₃-alkyl groups and-   R_(d) denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl,    tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group, by-   f) reacting a phosphonic ester of formula

wherein

-   R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl    group,-   R_(d) denotes a cyclopropylmethyl, cyclobutyl, cyclopentyl,    tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group and-   R¹ and R² each independently of one another denote a C₁₋₄-alkyl    group,    with the hydrogen sulphite adduct of formula

wherein

-   M⁺ denotes a cation, for example the sodium ion or a proton,-   R_(b) denotes a methyl, ethyl, isopropyl, cyclopropyl,    2-methoxyethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl-methyl,    tetrahydrofuran-3-yl-methyl, tetrahydropyran-4-yl or    tetrahydropyran-4-yl-methyl group,-   R_(c) denotes a methyl, ethyl or 2-methoxyethyl group or-   R_(b) and R_(c) together with the nitrogen atom to which these    groups are bound denote a morpholino or homomorpholino group    optionally substituted by one or two C₁₋₃-alkyl groups,    in the manner of a Wittig-Horner-Emmons reaction.

The reaction (a) of 7-chloro-6-nitro-3H-quinazolin-4-one (VII) with aprimary amine of formula (XV) for preparing a compound of formula (X) iscarried out in a suitable solvent, for example in acetonitrile, dioxane,THF, or mixtures thereof, e.g. in a mixture of acetonitrile, dioxane andin the presence of 1-2 equivalents POCl₃, at a temperature of 50 to 80°C.

The conversion (b) of a compound of formula (X) into the sulphonylderivative of formula (XIII) is carried out in a suitable solvent, forexample in acetonitrile, dioxane, THF, DMF, dimethylacetamide (DMA),N-methylpyrrolidone (NMP) or mixtures thereof, e.g. in a mixture of DMFand NMP by the addition of 1 to 2 equivalents of a correspondingsulphinic acid salt, for example the sodium salt of benzenesulphinicacid, at a temperature between 50° C. and the boiling temperature of thesolvent used, preferably at a temperature between 80 and 100° C.

The conversion (c) of the sulphonyl derivative of formula (XIII) into acompound of formula (XI) is carried out in a suitable solvent, forexample in acetonitrile, dioxane, THF, DMF, DMA, diglyme, tert-butanolor mixtures thereof, by the addition of 1 to 1.5 equivalents of analcohol of formula R_(d)—OH (XVI) and subsequent batchwise addition of 2to 4 equivalents of a strong base, for example powdered NaOH, KOH orLiOH, or potassium-tert.-butoxide, sodium-tert.-butoxide,lithium-tert.-butoxide, potassium-tert.-amylate, sodium-tert.-amylate orlithium-tert.-amylate as a solid or by dropwise addition of a solutionof these bases in tert. butanol, THF or DMF, at a temperature between 0and 100° C., preferably between 10 and 50° C., initially choosing a lowtemperature and raising the temperature after the addition of the baseto complete the reaction.

The reduction (d) of a compound of formula (XI) to the amino derivativeof formula (XII) is preferably carried out by catalytic hydrogenationwith hydrogen in the presence of a catalyst such as Raney nickel,palladium/charcoal or platinum in a solvent such as methanol, ethanol,ethyl acetate, DMF, DMA, NMP, DMF/acetone or DMF/methanol, optionallywith the addition of an acid such as acetic acid or an acid salt attemperatures between 0 and 100° C., for example at temperatures between0 and 80° C., but preferably at a temperature between 20 and 50° C., andunder a hydrogen pressure of 1 to 10 bar, for example 1 to 7 bar, butpreferably at a pressure of from 3 to 5 bar.

The conversion (e) of the amino derivative of formula (XII) into thephosphonic ester of formula (III) is carried out by reacting with1.0-2.0 equivalents of a di-(C₁₋₄-alkyl)-phosphonoacetic acid,preferably with diethylphosphonoacetic acid, in a suitable solvent suchas THF, DMF, toluene, ethyl acetate, methyl-tert.-butylether (MTBE) ormixtures thereof, e.g. in MTBE/THF, after corresponding activation attemperatures between 0° C. and 100° C. The activation may be carried outusing any of the current methods of amide linking, i.e. for example with1,1-carbonyldiimidazole, 1,1-carbonylditriazole, DCC(N,N-dicyclohexylcarbodiimide), EDC(N′-(dimethylaminopropyl)-N-ethylcarbodiimide), TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,thiazolidine-2-thione, or by conversion into the corresponding acidchloride, possibly using thionyl chloride or phosphorus oxychloride.Optionally the activation is carried out using organic bases such astriethylamine or pyridine, while DMAP (dimethylaminopyridine) mayadditionally be added.

The reaction (f) of the phosphonic ester of formula (III) with thehydrogen sulphite adduct of formula (XIV) is carried out in a suitablesolvent such as methanol, ethanol, THF, DMF, toluene, ethyl acetate andacetonitrile or mixtures thereof or in a binary or ternary mixture withwater, preferably in ethanol or ethanol/water, with the addition of asuitable base, e.g. sodium carbonate, lithium hydroxide, sodiumhydroxide or potassium hydroxide, optionally with the addition of astabilising salt such as lithium chloride, at a temperature of 0° C.-50°C., using 1-2 equivalents, preferably 1.2-1.6, e.g. 1.4 equivalents ofthe hydrogen sulphite adducts in aqueous solution.

Preferred embodiments of the process according to the invention with allthe partial steps (a) to (f) as well as the partial aspects B, C and Drelate to the preparation of compounds of formula (I), wherein

-   R_(a) denotes a 3-chloro-4-fluorophenyl group and R_(b), R_(c) and    R_(d) are defined as mentioned in embodiment A (embodiment F), or-   R_(b) and R^(c) in each case denote a methyl group and R_(a) and    R_(d) are defined as mentioned in embodiment A (embodiment H), or-   R_(a) denotes a 3-chloro-4-fluorophenyl group, R_(b) and R^(c) each    denote a methyl group and R_(d) are defined as mentioned in    embodiment A (embodiment I), or-   R_(d) denotes a tetrahydrofuran-3-yl or tetrahydropyran-4-yl group    and R_(a), R_(b) and R_(c) are defined as mentioned in embodiment A    (embodiment J), or-   R_(a) denotes a 3-chloro-4-fluorophenyl group, R_(b) and R^(c) in    each case denote a methyl group and-   R_(d) denotes a tetrahydrofuran-3-yl or tetrahydropyran-4-yl group    (embodiment K), or-   R_(a) denotes a 3-chloro-4-fluorophenyl group, R_(b) and R^(c)    together with the nitrogen atom to which these groups are bound    denotes a morpholine group and-   R_(d) denotes a tetrahydrofuran-3-yl or tetrahydropyran-4-yl group    (embodiment L), or-   R_(a) denotes a 3-chloro-4-fluorophenyl group, R_(b) and R^(c)    together with the nitrogen atom to which these groups are bound    denotes a homomorpholine group and-   R_(d) denotes a tetrahydrofuran-3-yl or tetrahydropyran-4-yl group    (embodiment M),-   while R_(a), R_(b), R_(c) and R_(d) in partial steps (a) to (f), in    each case corresponding to embodiments F to M, assume the meanings    given therein.

The process according to the invention is used to particular advantageto prepare the compound

4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,or the corresponding R-enantiomer.

The aminocrotonylamino-substituted quinazoline derivatives of formula(I) obtained by the process according to the invention may subsequentlybe converted by known methods into the salts thereof, particularly intophysiologically acceptable salts, for example into fumarates, tartratesor maleates. The conversion of the compound4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineobtained according to the invention into the corresponding dimaleate ispreferred, as described in WO 2005/037824.

The following Examples are intended to illustrate the invention in moredetail:

EXAMPLE 1 4-(3-Chloro-4-fluoro-phenylamino)-7-chloro-6-nitro-quinazoline

20 g 7-chloro-6-nitro-3H-quinazolin-4-one are suspended in 80 mlacetonitrile and combined with 16.5 g phosphorus oxychloride. Then 10.8g triethylamine are slowly added dropwise and the mixture is heated toabout 80° C. After 5 hours a solution of 15.5 g 3-chloro-4-fluoroanilinein 100 ml dioxane is added dropwise and the mixture is stirred foranother hour. Then 80 ml of water is added, the mixture is cooled to 20°C. and made slightly alkaline with KOH solution. The suspension issuction filtered, washed with water and ethanol and dried at 50° C. invacuo.

Yield: 29.07 g (89.5% of theoretical/dioxane solvate) m.p.: 272-274° C.

EXAMPLE 24-(3-Chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline

500 g 4-(3-chloro-4-fluoro-phenylamino)-7-chloro-6-nitro-quinazoline and302 g (1.3 eq) benzenesulphinic acid sodium salt are suspended at 20° C.in 1500 ml DMF, heated to 90° C. and kept for 6 h at this temperature.After cooling the reaction mixture the suspension is suction filteredand the residue is rinsed with 1.5 l methanol, 10 l water and 0.5 lmethanol. The residue is dried at 50° C. for about 12 h under reducedpressure.

Yield: 631.2 g (86.2% of theoretical/DMF solvate). m.p.: 284-286° C.

EXAMPLE 34-[(3-Chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline

810 g of4-(3-chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazolineand 175.5 g (S)-3-hydroxytetrahydrofuran (1.3 eq) are placed at 20° C.in 1.04 l tert-butanol and 198 ml DMF, 2556 g K-tert.-butoxide in THF(24%) (3.6 eq) are added dropwise at 20° C. and then stirred for 4 h at25° C. After a further 2 h at 40° C. the mixture is heated to 45° C. forabout 2 h. 2.8 l of water are added and then about 3 l solvent aredistilled off under reduced pressure. 2.8 l water are added again andabout 900 ml solvent are distilled off under reduced pressure. After theaddition of 1.6 l methanol the mixture is cooled to 20° C. Thesuspension is suction filtered and rinsed with a mixture of 3.2 l waterand 1.6 l methanol. The residue is dried overnight at 50° C. underreduced pressure.

Yield: 598.6 g (89.6% of theoretical). m.p.: 238-240° C.

EXAMPLE 44-[(3-Chloro-4-fluorophenyl)amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline

100 g of4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazolineare hydrogenated in 400 ml DMF in the presence of 33.1 g Raney nickeland 18.7 g ammonium chloride at 40° C., until the calculated amount ofhydrogen has been taken up. The catalyst is filtered off and thefiltrate is added dropwise to 1.2 l water. The suspension is stirred for2.5 h at 0° C., suction filtered and washed with 500 ml of water. Theresidue is dried overnight at 55° C. under reduced pressure.

Yield: 84.36 g (97.1% of theoretical). m.p.: 120-130° C.

EXAMPLE 5 Diethyl{[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonate

3.58 kg 1,1-carbonyldiimidazole (22.16 mol) are placed in 12.8 l oftetrahydrofuran and combined at 40° C. with 4.52 kg (22.16 mol)diethylphosphonoacetic acid, dissolved in 6.5 l tetrahydrofuran. Themixture is stirred for 30 minutes at 40° C. The solution thus obtainedis designated solution A.

6.39 kg (17.05 mol) ofN⁴-(3-chloro-4-fluoro-phenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamineare placed in 26.5 l tetrahydrofuran and combined at 40° C. withsolution A and stirred for 2 hours at 30° C. 64 l oftert.-butylmethylether are added to the suspension and after cooling to20° C. the precipitate is removed by centrifuging. It is washed with amixture of 16 l tetrahydrofuran and 16 l tert.-butylmethylether and thenwith 32 l water and dried at 50° C.

Yield: 6.58 kg (69.8%) white crystals. Content: HPLC 99.1 Fl %

EXAMPLE 6 Dimethylaminoacetaldehyde-Hydrogen Sulphite Adduct

40 g of dimethylaminoacetaldehyde diethylacetal are heated to 40° C. ina mixture of 48 g conc. hydrochloric acid and 20 ml of water for 3 h.Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodiumhydrogen sulphite solution) is added dropwise and the mixture is stirredfor 1 h. 200 ml of ethanol are added and then the mixture is stirred for2 h at 0° C. The suspension is suction filtered, washed with 160 ml ofethanol and dried at 45° C. in vacuo.

Yield: 42.5 g (89.6% of theoretical) decomp.: from 180° C.

EXAMPLE 7 (E)-4-Dimethylamino-but-2-enoicacid-[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-yl]-amide

10 g of diethyl{[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonateand 0.8 g lithium chloride are suspended in 60 ml of ethanol and cooledto −5° C. 11 g of 45% potassium hydroxide solution is added dropwisefirst of all and then 4.8 g dimethylaminoacetaldehyde-hydrogen sulphiteadduct in 48 ml of water is added. The reaction solution is stirred for1 h and then 60 ml of water are added. The suspension is suctionfiltered, washed with 40 ml of water and dried in vacuo at 45° C.

Yield: 8 g (91% of theoretical) m.p.: 100-102° C.

1. A compound of the formula

wherein R_(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenylgroup and R³ denotes a C₁₋₄-alkyl group wherein the hydrogen atoms maybe wholly or partly replaced by fluorine atoms, or a phenyl groupoptionally substituted by one to three substituents selected fromC₁₋₃-alkyl groups, halogen atoms, cyano or nitro groups, wherein thesubstituents may be identical or different.
 2. A compound of formula(XIII) according to claim 1, wherein R³ denotes the p-toluenesulphonyl,p-bromo-benzenesulphonyl, phenyl, p-nitro-benzenesulphonyl,methylsulphonyl, trifluoromethylsulphonyl, nonafluorobutylsulphonyl or2,2,2-trifluoroethanesulphonyl group.
 3. A compound of formula (XIII)according to claim 1, wherein if R³ denotes a phenyl group, it isoptionally substituted by one to three substituents selected fromC₁₋₃-alkyl groups, fluorine, chlorine, bromine, cyano or nitro groups,wherein the substituents may be identical or different.
 4. A compound offormula (XIII) according to claim 1 selected from among: (1)4-(3-chloro-4-fluoro-phenylamino)-7-(4-methyl-phenylsulphonyl-)-6-nitro-quinazoline,(2)4-(3-chloro-4-fluoro-phenylamino)-7-(4-bromo-phenylsulphonyl)-6-nitro-quinazoline,(3)4-(3-chloro-4-fluoro-phenylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline,(4)4-(3-chloro-4-fluoro-phenylamino)-7-(4-nitro-phenylsulphonyl)-6-nitro-quinazoline,(5)4-(3-chloro-4-fluoro-phenylamino)-7-(methylsulphonyl)-6-nitro-quinazoline,(6)4-(3-chloro-4-fluoro-phenylamino)-7-(trifluoromethylsulphonyl)-6-nitro-quinazoline,(7)4-(3-chloro-4-fluoro-phenylamino)-7-(nonafluorobutylsulphonyl)-6-nitro-quinazoline,(8)4-(3-chloro-4-fluoro-phenylamino)-7-(2,2,2-trifluoroethanesulphonyl)-6-nitro-quinazoline(9) 4-(benzylamino)-7-(4-methyl-phenylsulphonyl-)-6-nitro-quinazoline,(10) 4-(benzylamino)-7-(4-bromo-phenylsulphonyl)-6-nitro-quinazoline,(11) 4-(benzylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline, (12)4-(benzylamino)-7-(4-nitro-phenylsulphonyl)-6-nitro-quinazoline, (13)4-(benzylamino)-7-(methylsulphonyl)-6-nitro-quinazoline, (14)4-(benzylamino)-7-(trifluoromethylsulphonyl)-6-nitro-quinazoline, (15)4-(benzylamino)-7-(nonafluorobutylsulphonyl)-6-nitro-quinazoline, (16)4-(benzylamino)-7-(2,2,2-trifluoroethanesulphonyl)-6-nitro-quinazoline,(17)4-(1-phenylethylamino)-7-(4-methyl-phenylsulphonyl-)-6-nitro-quinazoline,(18)4-(1-phenylethylamino)-7-(4-bromo-phenylsulphonyl)-6-nitro-quinazoline,(19) 4-(1-phenylethylamino)-7-(phenylsulphonyl)-6-nitro-quinazoline,(20)4-(1-phenylethylamino)-7-(4-nitro-phenylsulphonyl)-6-nitro-quinazoline,(21) 4-(1-phenylethylamino)-7-(methylsulphonyl)-6-nitro-quinazoline,(22)4-(1-phenylethylamino)-7-(trifluoromethylsulphonyl)-6-nitro-quinazoline,(23)4-(1-phenylethylamino)-7-(nonafluorobutylsulphonyl)-6-nitro-quinazolineand (24)4-(1-phenylethylamino)-7-(2,2,2-trifluoroethanesulphonyl)-6-nitro-quinazoline.